The major aims of the study are (l) to determine the (optimal) length of time during which drug treatment for depression should be continued following an acute treatment phase; (2) to assess the efficacy of two dosages of desipramine (DMI) vs. a placebo during continuation treatment; (3) to establish the direction and nature of changes in biological markers at different stages during the treatment of depressive illness; (4) to examine withdrawal phenomena following discontinuation of DMI after one and two years of continuous use; and (5) to determine the extent to which measures of social support and life events are related to treatment outcome. Subjects for the study will be l70 acutely depressed patients (diagnosed by RDC and DSM III criteria). The duration of the study will be approximately two years, with subjects going through an initial one-week screening period, a two eight-week acute treatment phase, a two-month stabilization period, an eight-month drug continuation phase, and a twelve-month prophylactic phase. Experimental treatment conditions will consist of (l) the administration of a "high" vs. "low" dose of DMI, as well as placebo, during the continuation phase and (2) the discontinuation of medication for one-half the subjects on both high and low doses of DMI during the prophylactic phase. Biological and psychological/behavioral measures will be obtained at baseline and at regular intervals throughout the course of the study. Biological measures to be utilized include MHPG and its circadian pattern, Dexamethasone Suppression Test, TRH Stimulation Test, Ritalin Stimulation Test, platelet Alpha2 receptor binding, and DMI blood levels. Psychological/behavioral measures include Clinical Global Impressions, the Brief Psychiatric Rating Scale, the Hamilton Depression and Anxiety Scales, the Beck Depression Inventory, the Carroll Self-Rating Scale for Depression, and the Profile of Mood States. Also to be used are an adverse experiences inventory, the Abnormal Involuntary Movements Scale, a social network questionnaire, and a life events inventory. A long-term objective of the project is the validation of biochemical markers as aids to the diagnosis of the various affective disorders and as predictors of treatment response and relapse.